Genomic data hold the promise of revolutionizing our understanding and treatment of human disease. Multiple barriers stand between the acquisition of the data and realizing these and other benefits. Rapid accumulation of genomic data far exceeds our capacity to reliably interpret genomic variation. New developments in artificial intelligence and machine learning, combined with increased computing power and domain knowledge, provide hope for the deployment of enhanced computational tools in both basic research and clinical practice. Use of these methods critically depends upon reliable characterization of their performance. The Center for Critical Assessment of Genome Interpretation (C-CAGI) will address these needs, through objective evaluation of the state of the art in relating human genetic variation and health. CAGI has had five editions since 2010 with 50 challenges posed to the community taken on by hundreds of predictors, leading to scores of publications about prediction methods and their assessment. We propose for C-CAGI to continue to advance the field of variant interpretation through the following Specific Aims: 1. Develop community experiments to evaluate the quality of computational methods for interpreting genomic variation data. C-CAGI will conduct community experiments in which participants make bona fide blinded predictions of disease related phenotypes on the basis of genomic data. We will engage a diverse predictor community to spur innovation. The CAGI Ethics Forum will vet studies to ensure that privacy and sharing maintain the highest standards and will educate the community. 2. Assess the quality of current computational methods for interpreting genomic variation data; highlight innovations and progress at interactive conferences. Predictions will be evaluated by independent assessors, who will be supported by new assessment approaches from C-CAGI. Results will be presented at CAGI experiment conferences with deep technical engagement, which will be interleaved with reflective CAGI? meetings that create an environment for a comprehensive evaluation of the field, facilitating identification of major bottlenecks and problems faced by the current genome interpretation approaches. 3. Broadly disseminate the results and conclusions from the CAGI experiments and analysis. C-CAGI will outreach to the broader scientific and clinical community through its publications, and the creation of a calibrated reference integrated into the most common workflows for ready adoption. CAGI will also be represented at international meetings with presentations and workshops. 4. Operate effectively and responsively. C-CAGI will operate efficiently as it closely interacts with hundreds of participants. CAGI will build upon a robust information infrastructure that securely facilitates data dissemination, prediction submission, and assessment.